Elizabeth Margolskee
Cornell University
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Featured researches published by Elizabeth Margolskee.
PLOS ONE | 2013
Elizabeth Margolskee; Vaidehi Jobanputra; Suzanne K. Lewis; Bachir Alobeid; Peter H. Green; Govind Bhagat
Enteropathy-associated T-cell lymphomas (EATL) are rare and generally aggressive types of peripheral T-cell lymphomas. Rare cases of primary, small intestinal CD4+ T-cell lymphomas with indolent behavior have been described, but are not well characterized. We describe morphologic, phenotypic, genomic and clinical features of 3 cases of indolent primary small intestinal CD4+ T-cell lymphomas. All patients presented with diarrhea and weight loss and were diagnosed with celiac disease refractory to a gluten free diet at referring institutions. Small intestinal biopsies showed crypt hyperplasia, villous atrophy and a dense lamina propria infiltrate of small-sized CD4+ T-cells often with CD7 downregulation or loss. Gastric and colonic involvement was also detected (n = 2 each). Persistent, clonal TCRβ gene rearrangement products were detected at multiple sites. SNP array analysis showed relative genomic stability, early in disease course, and non-recurrent genetic abnormalities, but complex changes were seen at disease transformation (n = 1). Two patients are alive with persistent disease (4.6 and 2.5 years post-diagnosis), despite immunomodulatory therapy; one died due to bowel perforation related to large cell transformation 11 years post-diagnosis. Unique pathobiologic features warrant designation of indolent small intestinal CD4+ T-cell lymphoma as a distinct entity, greater awareness of which would avoid misdiagnosis as EATL or an inflammatory disorder, especially celiac disease.
Head and Neck Pathology | 2016
Vignesh Shanmugam; Elizabeth Margolskee; Michael J. Kluk; Tamara Giorgadze; Attilio Orazi
Rosai–Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy is a rare histiocytic proliferation that is generally considered to be reactive with a benign clinical course. The etiology of RDD is very poorly understood. Recent studies have shown frequent BRAF, NRAS, KRAS, and PIK3CA activating mutations in several histiocytic neoplasms highlighting the emerging importance of the RAF/MEK/ERK pathway in the pathogenesis of these diseases. Here we report a case of Rosai–Dorfman disease involving the submandibular salivary gland with a KRAS K117N missense mutation discovered by next-generation sequencing. These results suggest that at least a subset of RDD cases may be clonal processes. Further mutational studies on this rare histiocytic disease should be undertaken to better characterize its pathogenesis as well as open up potential avenues for therapy.
British Journal of Haematology | 2018
Arianna Di Napoli; Preti Jain; Enrico Duranti; Elizabeth Margolskee; Walter Arancio; Fabio Facchetti; Bachir Alobeid; Fabio Santanelli di Pompeo; Mahesh Mansukhani; Govind Bhagat
Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is an uncommon neoplasm occurring in women with either cosmetic or reconstructive breast implants (Clemens et al, 2016). Until now, most studies have focused on defining the clinico-pathological features of BI-ALCL, leading to its inclusion as a new provisional entity, a subtype of anaplastic lymphoma kinase (ALK)-negative ALCL, in the revised World Health Organization classification of lymphoid malignancies (Swerdlow et al, 2016). BI-ALCL is characterized by the presence of CD30 large atypical lymphocytes frequently confined to the peri-implant seroma fluid. Nevertheless, solid infiltrating masses and cases pursuing an aggressive clinical course have been reported. The surgical and pathological staging system designed by Clemens et al (2016) suggests that BI-ALCL has a pattern of progression similar to that of solid tumours rather than non-Hodgkin lymphomas, and that the effusionand solid-types might represent different stages of the same disease rather than two distinct variants. The molecular pathogenesis and mechanisms of progression of BI-ALCL, however, remain largely unknown, thus limiting the identification of biomarkers that enable disease prognostication and optimal treatment. Hence, we performed targeted next generation sequencing of seven BI-ALCL, identified in the archives of three institutions over 7 years, to investigate the presence of underlying somatic mutations. Informed consent was obtained from patients and the study was performed in accordance with the Declaration of Helsinki. DNA extracted from micro-dissected tumour cells of formalin-fixed paraffin-embedded BI-ALCL samples (QIAamp DNA Mini kit; Qiagen, Germantown, MD, USA) was used to prepare DNA libraries (Sureselect kit; Agilent Technologies, Santa Clara, CA, USA). Sequencing was performed on a HiSeq2500 (Illumina, San Diego, CA, USA) using a panel of 465 cancerassociated genes (Table SI). The sequence data were aligned to the human reference genome (hg19) and variants were identified using NextGENe (SoftGenetics, State College, PA, USA). The average read depth of the samples was 4009 (Table SII). Somatic mutations were identified by comparison of variants detected in lymphoma with those from matched constitutional DNA. Common variants (>1% frequency) present in the 1000 genomes database, and the database of Columbia University were removed. Somatic mutations were classified using the prior literature, and two different prediction algorithms (SIFT http://sift.bii.a-star.edu.sg and Polyphen-2 [PP2] http://genetics.bwh.harvard.edu/pph2/). The exonic somatic variants were confirmed by bidirectional Sanger sequencing using Big-Dye terminators v3.1 (Applied Biosystems, Carlsbad, CA, USA). The clinical and pathological features of the patients are summarized in Table I. Informative results were obtained in five of seven cases (Table SII); analysis failed in two cases due to the poor quality of DNA. Five somatic variants affecting four genes were identified in two cases: one intronic and four within coding regions (Fig 1 and Table SIII). A STAT3 missense variant (p.S614R) affecting the SH2 domain, which mediates STAT3 dimerization, was detected in one of these two BI-ALCLs. JAK/STAT signalling is implicated in cell proliferation, differentiation and apoptosis, and aberrant activation of STAT3 has been reported in several human cancers associated with persistent immune stimulation and/or inflammation. Notably, the gain-of-function mutation (S614R) was recently described in one BI-ALCL (Blombery et al, 2016), and has been reported in angioimmunoblastic T cell lymphomas, chronic lymphoproliferative disorders of natural killer cells, and T-cell large granular lymphocyte leukaemias (Odejide et al, 2014). Moreover, gain-of-function mutations in STAT3 have been reported in 18% of systemic ALK-negative ALCLs and 5% of cutaneous ALCLs (Crescenzo et al, 2015). An in vitro study using BI-ALCL-derived cell lines also showed activation of the JAK/STAT pathway through autocrine production of interleukin 6, suggesting a possible pathogenic mechanism (Lechner et al, 2012). A frameshift deletion causing a premature stop codon in SOCS1 (p.P83Rfs*20) was detected in the BI-ALCL harbouring the STAT3 mutation. SOCS1 is a negative feedback regulator of the JAK/STAT pathway. The p.P83Rfs*20 mutation deletes the C-terminal SOCS box domain and partially deletes the SH2 domain, which downregulates the kinase activity of JAK. Loss-of-function mutations of SOCS1, leading to constitutive activation of JAK/STAT signalling, have been described in B-cell lymphomas and in classical Hodgkin lymphomas (Mottok et al, 2009). Moreover, SOCS1 was found to be silenced by miR-155 in ALK-negative ALCL (Merkel et al, 2015). Mutations in STAT3 and SOCS1 suggest that deregulated activation of the JAK/STAT pathway may contribute to the development of BI-ALCL. A missense mutation of TP53 (p.D259Y) affecting the DNA binding domain was also observed in the Correspondence
Cancer Cytopathology | 2015
Marcela Salomao; Tamas A. Gonda; Elizabeth Margolskee; Vasco Eguia; Helen Remotti; John M. Poneros; Amrita Sethi; Anjali Saqi
Brush cytology is the initial intervention when evaluating biliary strictures. Biliary brush cytology is known for its low sensitivity (but high specificity) and may be accompanied by biopsies and/or fluorescent in situ hybridization (FISH) to improve diagnostic yield. This study aimed to identify features to enhance cytological sensitivity, and assess which sampling method(s) improve identification of pancreatobiliary adenocarcinomas (PBCa).
Oncotarget | 2016
Elizabeth Margolskee; Vaidehi Jobanputra; Preti Jain; Jinli Chen; Karthik A. Ganapathi; Odelia Nahum; Brynn Levy; Julie Morscio; Vundavalli V. Murty; Thomas Tousseyn; Bachir Alobeid; Mahesh Mansukhani; Govind Bhagat
Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development.
Modern Pathology | 2018
Elizabeth Margolskee; Geoff Mikita; Bryan Rea; Adam Bagg; Zhuang Zuo; Yi Sun; Maitrayee Goswami; Sa A. Wang; Jean Oak; Daniel A. Arber; M. Brandon Allen; Tracy I. George; Heesun J. Rogers; Eric D. Hsi; Robert P. Hasserjian; Attilio Orazi
The 2016 WHO update changed the diagnostic criteria for myeloid neoplasms with erythroid predominance, limiting the diagnosis of acute myeloid leukemia to cases with ≥20% blasts in the bone marrow or peripheral blood. Although acute myeloid leukemia with ≥50% erythroid cells has historically been presumed to represent acute myeloid leukemia with myelodysplasia-related changes, this hypothesis has never been systematically examined. We sought to investigate the clinicopathologic, cytogenetic, and molecular features of acute myeloid leukemia with erythroid predominance to subclassify cases as defined by the 2016 WHO. We retrospectively identified patients with ≥50% erythroid precursors and either ≥20% bone marrow blasts or ≥20% peripheral blood blasts at the time of initial diagnosis at seven major academic centers. Laboratory and clinical data were obtained. Patients were then reclassified according to 2016 WHO guidelines. A matched control group was also obtained. We identified 146 patients with acute myeloid leukemia with erythroid predominance (62% M, average age: 62 y, range: 5–93 y). Of these, 91 were acute myeloid leukemia with myelodysplasia-related changes, 20 (14%) were therapy-related myeloid neoplasm, 23 (16%) acute myeloid leukemia, not otherwise specified, and ten acute myeloid leukemia with recurrent cytogenetic/molecular abnormalities. The bone marrow blast count ranged from 9–41%. There was no difference in survival for patients with erythroid predominance compared to patients with acute myeloid leukemia without erythroid proliferations. In a multivariable analysis, cytogenetic risk was the only significant predictor of survival. We find a significantly lower rate of FLT3 and RAS pathway alterations in acute myeloid leukemia with erythroid predominance compared to controls. Our study is one of the first to apply the 2016 WHO guidelines for classification of acute myeloid leukemia. We find acute myeloid leukemia with erythroid predominance is a heterogeneous group and that erythroid richness has no impact on overall survival.
Annual Review of Pathology-mechanisms of Disease | 2018
Marco Pizzi; Elizabeth Margolskee; Giorgio Inghirami
Peripheral T cell lymphomas (PTCLs) are highly heterogeneous tumors, displaying distinct clinical and biological features. The pathogenesis and normal counterpart of such entities have been elusive for decades. Recent studies have, however, disclosed key mechanisms of peripheral T cell transformation, including (a) the deregulation of signaling pathways controlling T cell development, differentiation, and maturation; (b) the remodeling of the peritumor microenvironment; and (c) the virus-mediated rewiring of T cell biology. Uncovering the molecular mechanisms of T cell transformation will help elucidate the peculiar clinical and pathological features of each PTCL entity and will lead to the characterization of novel antitumor therapies. These therapies will combine conventional and new-generation compounds with immune-modulating agents to ablate both the neoplastic cells and the tumor-supporting microenvironment. This review addresses the pathogenic mechanisms of PTCLs, with special attention paid to novel therapeutic strategies for the clinical management of such aggressive tumors.
Leukemia | 2018
Elizabeth Margolskee
To the editor: We read with interest the recent article by Patnaik et al. in Leukemia [1]. The authors describe a large cohort of patients with chronic myelomonocytic leukemia with progression to so-called “blast phase” CMML and demonstrate poor outcomes in this cohort. Although the authors reference WHO diagnostic criteria for “CMML blast phase” in their paper, the WHO classification does not recognize a “blast phase” CMML; rather, the presence of 20% or more blasts in bone marrow or peripheral blood constitutes progression to acute myeloid leukemia, which “belongs in the group of AML with myelodysplasia-related changes [2].” At present, “blast phase” terminology is limited to the myeloproliferative neoplasms and not used for myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Prior (albeit smaller) studies have found the prognosis of AML arising in patients with CMML is similar to AML-MRC, supporting its placement in this category [3]. This distinction between AML and “blast phase” may seem arbitrary, but precise, uniform nomenclature is important to facilitate communication between pathologists, clinicians, and patients. Coordinated use of terminology allows for establishment of international clinical trials and accurate epidemiological studies. The world is an increasingly cacophonic place; it is imperative that physicians speak the same language.
Haematologica | 2017
Elizabeth Margolskee; Spencer Krichevsky; Attilio Orazi; Richard T. Silver
Polycythemia vera (PV) is a clonal myeloproliferative neoplasm (MPN) almost always associated with mutations in JAK2 , most commonly the gain-of-function missense variant V617F. Results of recombinant interferon α-2b (rIFNα-2b) or pegylated rIFNα-2α (peg-rIFNα-2a) therapy in patients with PV
CytoJournal | 2017
Simon Sung; Anjali Saqi; Elizabeth Margolskee; John P. Crapanzano
Background: Thyroid follicular cells share similar cytomorphological features with parathyroid. Without a clinical suspicion, the distinction between a thyroid neoplasm and an intrathyroidal parathyroid can be challenging. The aim of this study was to assess the distinguishing cytomorphological features of parathyroid (including intrathyroidal) and Bethesda category IV (Beth-IV) thyroid follicular lesions, which carry a 15%–30% risk of malignancy and are often followed up with surgical resection. Methods: A search was performed to identify “parathyroid” diagnoses in parathyroid/thyroid-designated fine-needle aspirations (FNAs) and Beth-IV thyroid FNAs (follicular and Hurthle cell), all with diagnostic confirmation through surgical pathology, immunocytochemical stains, Afirma® analysis, and/or clinical correlation. Unique cytomorphologic features were scored (0-3) or noted as present versus absent. Statistical analysis was performed using R 3.3.1 software. Results: We identified five FNA cases with clinical suspicion of parathyroid neoplasm, hyperthyroidism, or thyroid lesion that had an eventual final diagnosis of the parathyroid lesion (all female; age 20–69 years) and 12 Beth-IV diagnoses (11 female, 1 male; age 13–64 years). The following cytomorphologic features are useful distinguishing features (P value): overall pattern (0.001), single cells (0.001), cell size compared to red blood cell (0.01), nuclear irregularity (0.001), presence of nucleoli (0.001), nuclear-to-cytoplasmic ratio (0.007), and nuclear chromatin quality (0.028). Conclusions: There are cytomorphologic features that distinguish Beth-IV thyroid lesions and (intrathyroidal) parathyroid. These features can aid in rendering correct diagnoses and appropriate management.